Among the most common and debilitating human birth defects are those that affect craniofacial tissues The last decade has witnessed the identification of numerous candidate regulatory genes that are expressed in regionally restricted patterns in the craniofacial primordia Among these are homeobox transcription factors that include the Dlx gene family In mammals there are three Type A Dlx genes (2,3,5) and three Type B Dlx genes (1,6,7) These genes are expressed in nested patterns in the primordia of the branchial arches as well as the olfactory and otic appatati We have made loss-of-function mutations of Dlxl, Dlx2, Dlxl&2 and Dlx5 in the mouse and found that these genes are essential for normal skeletal morphogenesis of the jaw apparatus and teeth, as well as the nasal and otic capsules Comparison of the Dlx-expression patterns with the morphological defects seen in the Dlx mutants suggests that there is a Dlx combinatorial code that specifies regional morphogenesis of the branchial arches and olfactory and otic apparati To evaluate our combinatorial model of Dlx function, we are studying craniofacial molecular and tissue patterning in Dlx compound mutants In addition, we will study the cellular and molecular mechanisms through which the Dlx genes regulate claniofacial development